Method of treating cachexia

ABSTRACT

Compounds of formula (I): ##STR1## and pharmaceutically acceptable salts thereof are valuable in the treatment of cachexia.

BACKGROUND TO THE INVENTION

The present invention relates to the use of a series oftriazolopyrimidine and pyrazolopyrimidine derivatives as therapeuticagents for the treatment of cachexia, and also provides certain suchcompounds as novel compositions of matter and provides processes for thepreparation of the aforesaid new compounds.

Certain of the triazolopyrimidine compounds used in the presentinvention are disclosed in Japanese Patent Application Kokai (i.e. aslaid open to public inspection prior to examination) No. Sho 51-141896,[Tokko (i.e. as oybkusged after exanubatuib) No. Sho 57-60356 ].Japanese Patent Application Kokai No. Sho 52-116497 (Tokko No. Sho58-437). Japanese Patent Application Kokai No. Sho 53-53697, U.S. Pat.No. 4,007,189 and the Journal of Medicinal Chemistry, 23, 927-937(1980). In addition certain ketonic compounds of this type weredisclosed orally at a meeting of the Pharmaceutical Society of Japan on28-30 August 1979 and were reported to be of use in the treatment ofischemic heart disease. However, it has not previously been found thatany of these known compounds have properties which might render themsuitable for the treatment of cachexia.

"Cachexia" is the name given to a generally weakened condition of thebody or mind resulting from any debilitating chronic disease. Thesymptoms include severe weight loss, anorexia and anemia. Cachexia isnormally associated with neoplasmic diseases, chronic infectiousdiseases or thyroiditis, and is a particular problem when associatedwith cancerous conditions.

Indeed, it has been reported that a large proportion of the deathsresulting from cancer are, in fact, associated with cachexia, as alsoare various other problems commonly experienced by cancer patients, suchas respiratory insufficiency, cardiac failure, diseases of the digestiveorgans, hemorrhaging and systemic infection [U. Cocchi,Strahlentherapie, 69, 503-520 (1941); K. Utsumi et al., Jap. J. CancerClinics, 7, 271-283 (1961)].

Cancer associated cachexia, which decreases the tolerance of cancerpatients to chemotherapy and radiotherapy is said to be one of theobstacles to effective cancer therapy [J. T. Dwyer, Cancer, 43,2077-2086 (1979); S. S. Donaldson et al., Cancer, 43, 2036-2052 (1979)].In order to overcome these problems, it used to be common for cancerpatients with cachexia to receive a high fat and high sugar diet, orthey used to be given high calorie nutrition intravenously. However, ithas been reported that symptoms of cachexia were rarely alleviated bythese regimens [M. F. Brenann, Cancer Res., 37, 2359-2364 (1977); V. R.Young, Cancer Res., 37, 2336-2347 (1977)].

There are several papers referring to the causes of cachexia. Thus, ithas been reported that, in cachexia associated with infection bybacteria or protozoa, certain humoral factors, such as cachectin/TNF(Tumor Necrosis Factor), interleukin I or γ-interferon, may suppress theactivity of enzymes such as lipoprotein lipase (E.C.3.1.1.34), which isan essential enzyme for triglyceride metabolism, and acetyl CoAcarboxylase and fatty acid synthetase, which are rate determiningenzymes in fatty acid synthesis. The same paper also points out that anydisorder involving the metabolism of fat may lead the patients toexperience severe waste and weight loss [M. Kawakami et al., J. Exp.Med., 154, 631-639 (1981); B. Beutler et al., Nature, 320, 584-588(1986); B. Beutler et al., J. Immunol., 135, 3969-3971 (1985); R.Kurzrock et al., J. Exp. Med., 164, 1093-1101 (1986); P. H. Pekala etal., Proc. Natl. Acad. Sci. USA, 80, 2743-2747 (1983); S. R. Price etal., Arch. Biochem. Biophys., 251, 738-746 (1986); M. Kawakaml Med.Immunol. 14. 187-190 (1987); J. S. Patton et al., Proc. Natl. Acad. Sci.USA, 83, 8313-8317 (1986)].

On the other hand, it is well known that cancer associated cachexiaoften results in the depletion of stored body-fat. This depletion is oneof the major causes of systemic waste in cancer patients. It has alsobeen suggested that this depletion of body-fat is brought about byincreasing the removal of fatty acids from the adipose tissue of cancerpatients [A.

Theologides, Cancer, 43, 2004-2012 (1979)]. Another paper has reported acorrelation between cachexia and a reduction in the activity of plasmalipoprotein lipase [H. Vlassara et al., Horm. Metabol. Res., 18, 698-703(1986)].

However, on the contrary, there has also been reported an increase inthe activity of the plasma lipoprotein lipase in cancer patientssuffering from cachexia [H. Masuno et al., Jap. J. Cancer Res., 76,202-207 (1985)].

Accordingly, the relationship between cachexia and lipoprotein lipasehas so far not been definitely established, and there are, indeed,contradictory indications as to whether or not it might be implicated.

We have now discovered that lipoprotein lipase is a key enzyme incachexia therapy, and that the cachexia in mammals, and hence in humans,may be alleviated by the enhancement of the activity of this enzyme.This enzyme is able to hydrolyze triglyceride in the very low densitylipoprotein and the chylomicron to convert the circulating triglycerideto the stored form. We have accordingly provided certain compounds, someof which are new and some of which are known, but all of which have notpreviously been known to enhance the activity of lipoprotein lipase, andwhich, by such enhancement, have demonstrated the ability to alleviatethe effects of cachexia.

BRIEF SUMMARY OF INVENTION

Thus, the present invention provides a method of treating or alleviatingthe effects of cachexia by the administration to a mammal, which may behuman, suffering from cachexia of an effective amount of an activeagent, wherein the active agent is at least one enhancer of the activityof lipoprotein lipase selected from the group consisting of compounds offormula (I): ##STR2## in which: Y represents a group of formula ##STR3##the dotted line represents a carbon-carbon double bond or acarbon-carbon single bond and, if necessary, a hydrogen atom at one orboth of the carbon atoms which the bond links;

R¹ represents a hydrogen atom, a C₁ -C₅ alkyl group or a C₆ -C₁₀carbocyclic aryl group which is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (a),defined below;

R² represents a hydrogen atom or a halogen atom;

R³ represents a C₁ -C₅ alkyl group or a C₃ -C₇ cycloalkyl group;

R⁴ represents a hydrogen atom, a C₁ -C₅ alkyl group or a hydroxy group,or, but only when Y represents said group of formula (III) and saiddotted line represents a double bond, a halogen atom;

R⁵ represents a hydrogen atom, a C₁ -C₅ alkyl group, a hydroxy group, anoxygen atom or, but only when Y represents said group of formula (III)and said dotted line represents a double bond, a halogen atom; and

R⁶ represents a hydrogen atom, a C₁ -C₁₅ alkyl group, a C₁ -C₅ alkylgroup having at least one substituent selected from the group consistingof substituents (b), defined below, a C₃ -C₇ alkenyl group, a C₃ -C₅alkynyl group, a C₃ -C₁₀ cycloalkyl group, a C₆ -C₁₀ carbocyclic arylgroup which is unsubstituted or has at least one substituent selectedfrom the group consisting of substituents (a), defined below, or anaralkyl group in which the alkyl part is C₁ -C₃ and is unsubstituted orhas at least one hydroxy substituent, and the aryl part is a C₆ -C₁₀carbocyclic aryl group which is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (c),defined below;

substituents (a)

C₁ -C₅ alkyl groups, halogen atoms, C₁ -C₅ alkoxy groups and sulfamoylgroups;

substituents (b)

halogen atoms, hydroxy groups, mercapto groups, dialkylamino groups inwhich each alkyl part is C₁ -C₅ and is unsubstituted or has at least onehydroxy substituent, heterocyclic groups as defined below, phenoxygroups, C₁ -C₅ alkoxy groups, C₁ -C₅ hydroxyalkoxy groups, benzoylgroups, substituted benzoyl groups having at least one substituentselected from the group consisting of substituents (d), defined below,benzoyloxy groups, substituted benzoyloxy groups having at least onesubstituent selected from the group consisting of substituents (d),defined below, and heterocycliccarbonyloxy groups in which theheterocyclic part has from 5 to 6 ring atoms of which 1 or 2 arenitrogen hetero-atoms;

substituents (c)

C₁ -C₅ alkyl groups, halogen atoms and C₁ -C₅ alkoxy groups;

substituents (d)

halogen atoms and C₁ -C₅ alkoxy groups;

said heterocyclic groups have from 5 to 6 ring atoms of which 1 is anitrogen atom through which the group is attached to the remainder ofthe molecule and 0, 1 or 2 are additional hetero-atoms selected from thegroup consisting of nitrogen and oxygen hetero-atoms, said group beingunsubstituted or having at least one C₁ -C₅ alkyl substituent;

and pharmaceutically acceptable salts thereof.

Of the compounds listed above, those compounds are novel in which Yrepresents the group of formula (III). and these new compounds also formpart of the present invention.

The invention also provides processes for preparing the novel compoundsof the present invention, as described in more detail hereafter.

DETAILED DESCRIPTION OF INVENTION

A class of compounds which may be used in the present invention, and allof which are previously known as described above, is those compounds offormula (Ia): ##STR4## in which: R¹ and R³ are as defined above;

R^(4') represents a hydrogen atom, a hydroxy group or a C₁ -C₅ alkylgroup;

R^(5') represents a hydrogen atom, a hydroxy group, an oxygen atom or aC₁ -C₅ alkyl group; and

R^(6') represents a hydrogen atom, a C₁ -C₁₅ alkyl group, a C₁ -C₅ alkylgroup having at least one substituent selected from the group consistingof substituents (b), defined above, a C₃ -C₇ alkenyl group, a C₃ -C₁₀cycloalkyl group, a C₆ -C₁₀ carbocyclic aryl group which isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (a), defined above, or an aralkyl group inwhich the alkyl part is C₁ -C₃ and the aryl part is a C₆ -C₁₀carbocyclic aryl group which is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (c),defined above;

and pharmaceutically acceptable salts thereof.

In the above formula (Ia), and also in following formula (Ib), thegroups shown as R^(4'), R^(4"), R^(5'), R^(5") and R^(6') correspond tothe groups shown in formula (I) as R⁴, R⁵ and R⁶, respectively, andhereafter, where examples are given of groups which may be representedby R⁴, R⁵ and R⁶, these examples apply mutatis mutandis to the groupsrepresented by R^(4'), R^(4"), R^(5'), R^(5") and R^(6').

Novel compounds of the present invention are those compounds of formula(Ib): ##STR5## in which: R¹, R², R³, R⁶ and the dotted line are asdefined above,

R^(4") represents a hydrogen atom, or, but only when the dotted linerepresents a double bond, a hydrogen atom or a halogen atom; and

R^(5") represents a hydrogen atom, or, but only when the dotted linerepresents a double bond, a hydrogen atom or a halogen atom;

and pharmaceutically acceptable salts thereof.

These novel compounds per se also form part of the present invention.

In the compounds of the invention, where R¹, R³, R⁴, R⁵, substituent(a), substituent (c) and/or the alkyl substituent on the heterocycliccarbonyloxy group included within substituent (b) represents an alkylgroup, this may be a straight or branched chain alkyl group containingfrom 1 to 5 carbon atoms. Examples of such groups include the methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl and pentylgroups. Of these, the straight and branched chain alkyl groupscontaining from 1 to 3 carbon atoms are preferred; and we most preferthat R¹ and/or R³ and/or R⁴ should represent a methyl group and that R₅should represent a methyl or ethyl group.

Where R¹ and/or R⁶ represents an aryl group, this is a carbocyclic arylgroup containing from 6 to 10 ring carbon atoms, for example, a phenylor naphthyl (1- or 2- naphthyl) group. This aryl group may besubstituted or unsubstituted and, if it is substituted, the substituentsare selected from the group consisting of substituents (a) defined aboveand exemplified below. There is, in general, no restriction on thenumber of substituents, except such as may be imposed by the number ofsubstitutable positions, although sometimes steric constraints mayfurther limit the number of such substituents; in general, the maximumnumber of substituents is 5 where the aryl group is a phenyl group and 7where the aryl group is a naphthyl group. More preferably, R¹ and/or R⁶represents a phenyl group, which is unsubstituted or which has at leastone substituent selected from the group consisting of: alkyl groupscontaining from 1 to 3 carbon atoms; halogen atoms; straight andbranched chain alkoxy groups containing from 1 to 3 carbon atoms; andsulfamoyl groups. Most preferably, R¹ represents a phenyl group, whichis unsubstituted or which has at least one substituent selected from thegroup consisting of halogen atoms and straight and branched chain alkoxygroups containing from 1 to 3 carbon atoms. R⁶ most preferablyrepresents a phenyl group, which is unsubstituted or which has at leastone substituent selected from the group consisting of halogen atoms andsulfamoyl groups. Where R¹ and/or R⁶ represents a substituted arylgroup, examples of such groups include: aryl groups substituted with astraight or branched chain alkyl group containing from 1 to 5 carbonatoms, such as the 4-methylphenyl, 4-ethylphenyl and 3-propylphenylgroups; halogen-substituted aryl groups, such as the 4-chlorophenyl,2,6-dichlorophenyl, 4-bromophenyl and 4-fluorophenyl groups; aryl groupssubstituted with a straight or branched chain alkoxy group containingfrom 1 to 5 carbon atoms, such as the 4-methoxyphenyl,3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-ethoxyphenyl and4-propoxyphenyl groups; and sulfamoyl-substituted aryl groups, such asthe 4-sulfamoylphenyl and 3-sulfamoylphenyl groups.

Examples of the groups and atoms which may be included in substituents(a) include:

(1) straight and branched chain alkyl groups containing from 1 to 5carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl and pentyl groups;

(2) halogen atoms, such as the chlorine, bromine and fluorine atoms;[similar atoms may be included within substituents (d)];

(3) straight and branched chain alkoxy groups having from 1 to 5 carbonatoms, such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy andpentyloxy groups; [similar groups may be included within substituents(d)]; and

(4) the sulfamoyl group.

Where R², R⁴ or R⁵ represents a halogen atom, this is preferably achlorine, bromine, iodine or fluorine atom, more preferably a chlorineor bromine atom.

Where R³ represents a cycloalkyl group, this has from 3 to 7 ring carbonatoms, and examples include the cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl groups. R³ preferably represents a cycloalkylgroup containing from 3 to 5 carbon atoms.

Where R⁶ represents an alkyl group, this is a straight or branched chainalkyl group containing from 1 to 15 carbon atoms, and examples of suchgroups include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, t-butyl, pentyl, isopentyl, t-pentyl, hexyl,1,3-dimethylbutyl, heptyl, octyl, 1,1,3,3-tetramethylbutyl, nonyl,decyl, undecyl, dodecyl, tridecyl, tetradecyl and penIadecyl groups. Ofthese, the alkyl groups having from 1 to 5 carbon atoms, examples ofwhich are as given in relation to R¹, may optionally be substituted.Where the alkyl group is substituted, the substituents are selected fromthe group consisting of substituents (b) defined above and exemplifiedbelow.

The groups and atoms which may be included in substituents (b) are:

(1) halogen atoms, such as the chlorine, bromine and fluorine atoms;

(2) the hydroxy group;

(3) the mercapto group;

(4) dialkylamino groups in which each alkyl part is C₁ -C₅ and isunsubstituted or has at least one hydroxy substituent, such as thedimethylamino, diethylamino, N-methyl-N-ethylamino,di(2-hydroxyethyl)amino, dipropylamino, N-methyl-N-propylamino,N-methyl-N-butylamino and dibutylamino groups;

(5) five- and six-membered cyclic amino groups (i.e. heterocyclic groupsjoined to the remainder of the molecule via the nitrogen atom), whichmay optionally contain a further 1 or 2 nitrogen and/or oxygen atoms inits ring and which may be unsubstituted or may be substituted with astraight or branched chain C₁ -C₅ alkyl group, such as the1-pyrrolidinyl, piperidino, morpholino and 4-methyl-1-piperazinylgroups;

(6) the phenoxy group

(7) straight and branched chain alkoxy and hydroxyalkoxy groupscontaining from 1 to 5 carbon atoms, such as the methoxy, ethoxy,2-hydroxyethoxy, hydroxymethoxy, 3-hydroxypropoxy, propoxy, isopropoxy,butoxy and pentyloxy groups;

(8) benzoyl groups which are unsubstituted or have at least onesubstituent selected from the group consisting of halogen atoms andstraight and branched chain alkoxy groups containing from 1 to 5 carbonatoms [i.e. substituents (d)], such as the benzoyl, 4-chlorobenzoyl and3,4,5-trimethoxybenzoyl groups;

(9) benzoyloxy groups which are unsubstituted or have at least onesubstituent selected from the group consisting of halogen atoms andstraight and branched chain alkoxy groups containing from 1 to 5 carbonatoms [i.e. substituents (d)], such as the benzoyloxy,4-chlorobenzoyloxy and 3,4,5-trimethoxybenzoyloxy groups; and

(10) saturated and unsaturated five- and six-membered heterocyclicacyloxy groups in which the heterocyclic ring may contain 1 or 2nitrogen atoms, such as the pyrrole-3-carbonyloxy,pyrrolidine-3-carbonyloxy, pyrazole-4-carbonyloxy,imidazole-4-carbonyloxy, imidazolidine-4-carbonyloxy,pyridine-3-carbonyloxy (i.e. nicotinoyloxy), pyridine-4-carbonyloxy(i.e. isonicotinoyloxy), piperidine-4-carbonyloxy andpyridazine-4-carbonyloxy groups.

R⁶ preferably represents a straight or branched chain alkyl groupcontaining from 1 to 12 carbon atoms or a C₁ -C₅ alkyl group which issubstituted as defined above. Where the alkyl group is substituted, itis a straight or branched chain alkyl group containing from 1 to 5carbon atoms and preferred examples of such substituents include: thehydroxy group; the dialkylamino group; the 5- and 6-memberedheterocyclic groups; the phenoxy group; the straight and branched chainalkoxy groups containing from 1 to 3 carbon atoms; the benzoyloxy groupwhich may be optionally substituted with a halogen atom or with astraight or branched chain alkoxy group containing from 1 to 3 carbonatoms; and the saturated and unsaturated 5- and 6-membered heterocyclicacyloxy groups containing 1 or 2 nitrogen atoms. Where the alkyl groupis substituted, it is most preferably a straight or branched chain alkylgroup containing from 1 to 5 carbon atoms and the substituent(s) areselected from the group consisting of the aforementioned hydroxy groups,dialkylamino groups, 5- and 6-membered heterocyclic groups, phenoxygroups, benzoyloxy groups which may optionally be substituted with ahalogen atom or a straight or branched chain alkoxy group containingfrom 1 to 3 carbon atoms, and saturated and unsaturated 5- and6-membered heterocyclic acyloxy groups in which the heterocyclic ringhas 1 or 2 nitrogen atoms.

Where R⁶ represents a substituted alkyl group, examples of such alkylgroups include: the halo-substituted alkyl groups, such as thechloroethyl (1- and 2-), 2,2,2-trichloroethyl, chloropropyl (1-, 2- and3-), bromoethyl (1- and 2-) and fluoropropyl (1-, 2- and 3-) groups;hydroxy-substituted alkyl groups, such as the 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl,2-hydroxy-1,1-dimethylethyl and 2,3-dihydroxypropyl groups;mercapto-substituted alkyl groups, such as the 2-mercaptoethyl and3-mercaptopropyl groups; dialkylamino-substituted alkyl groups in whichthe alkyl group of the dialkylamino part may optionally be substituted,such as the dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl,diethylaminoethyl, diethylaminopropyl, diethylaminobutyl,dibutylaminoethyl, dibutylaminopropyl and di(2-hydroxyethyl)aminopropylgroups; 5- and 6-membered heterocyclic-substituted alkyl groups, inwhich the heterocyclic part may optionally be substituted with astraight or branched chain alkyl group containing from 1 to 5 carbonatoms or which may optionally contain 1 or 2 nitrogen or oxygen atoms inthe ring, such as the 2-(1-pyrrolidinyl)ethyl, 3-(1-pyrrolidinyl)propyl,2-piperidinoethyl, 3-piperidinopropyl, 2-morpholinoethyl,3-morpholinopropyl, 2-(4-methyl-1-piperidinyl)ethyl and3-(4-methyl-1-piperazinyl)propyl groups; phenoxy-substituted alkylgroups, such as the 2-phenoxyethyl, 3-phenoxypropyl and2-phenoxy-1-methylethyl groups; alkoxy-substituted alkyl groups, inwhich the alkoxy group is a straight or branched chain alkoxy grouphaving from 1 to 5 carbon atoms, such as the ethoxymethyl, ethoxyethyl(1- and 2-) and ethoxypropyl (1-, 2- and 3-) groups;hydroxyalkoxy-substituted alkyl groups, in which the alkoxy group is astraight or branched chain alkoxy group having from 1 to 5 carbon atoms,such as the 2-(2-hydroxyethoxy)ethoxy, 2-(hydroxymethoxy)ethoxy,2-(3-hydroxypropoxy)ethoxy and 3-(3-hydroxypropoxy)propoxy groups;benzoyl-substituted alkyl groups, in which the benzoyl group mayoptionally be substituted with a halogen atom or with a straight orbranched chain alkoxy group containing from 1 to 5 carbon atoms, such asthe benzoylmethyl, benzoylethyl (1- and 2-), benzoylpropyl (1-, 2- and3-), 4-chlorobenzoylmethyl (1- and 2-) and3,4,5-trimethoxy-benzoylmethyl groups; benzoyloxy-substituted alkylgroups, in which the benzoyl group may optionally be substituted with ahalogen atom or with a straight or branched chain alkoxy groupcontaining from 1 to 5 carbon atoms, such as the benzoyloxymethyl,benzoyloxyethyl (1- and 2-), benzoyloxypropyl (1-, 2- and 3-),4-chlorobenzoyloxyethyl (1- and 2-), 3,4,5-trimethoxybenzoyloxyethyl (1-and 2-) and 3,4,5-trimethoxybenzoyloxypropyl (1-, 2- and 3-) groups;saturated and unsaturated 5- and 6-membered heterocyclic acyloxyalkylgroups containing 1 or 2 nitrogen atoms, such as thepyrrole-3-carbonyloxyethyl, pyrrolidine-3-carbonyloxyethyl,pyrazole-4-carbonyloxypropyl, imidazolidine-4-carbonyloxypropyl,imidazolidine-4-carbonyloxymethyl, pyridine-3-carbonyloxyethyl,pyridine-3-carbonyloxyethyl, pyridine-4-carbonyloxyethyl,piperidine-4-carbonyloxypropyl and pyridazine-4-carbonyloxyethyl groups.

Where R⁶ represents an alkenyl group, this contains from 3 to 7 carbonatoms and examples of such groups include the allyl, propenyl,methallyl, 2-butenyl, 3-butenyl, 3-pentenyl, 4-hexenyl and 5-heptenylgroups; of these, those alkenyl groups containing from 3 to 5 carbonatoms are preferred.

Where R⁶ represents an alkynyl group. This contains from 3 to 5 carbonatoms and examples of such groups include the 1-propynyl, 2-propynyl(i.e. "propargyl"), 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl and 4-pentynyl groups.

Where R⁶ represents a cycloalkyl group, this may have from 3 to 10 ringcarbon atoms, and examples of such groups include the cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl and perhydronaphthyl groups.

Where R⁶ represents an aralkyl group, the alkyl portion of this containsfrom 1 to 3 carbon atoms and the aryl portion is as generally definedabove in relation to the aryl groups which may be represented by R⁶, andmay be substituted or unsubstituted as defined in relation to such arylgroups. Examples of such aralkyl groups include the benzyl, phenethyl,α-methylbenzyl, 2-phenyl-1-methylethyl, 1-phenyl-1-methylethyl,phenylpropyl (1-, 2- and 3-), 1-naphthylmethyl and 2-naphthylmethylgroups. These aralkyl groups may be unsubstituted or the aryl (e.g.phenyl) part thereof may have at least one substituent selected from thegroup consisting of substituents (c), defined above, i.e. alkyl groups,halogen atoms and alkoxy groups; examples of these are as given inrelation to the same groups which may be included in substituents (a).The alkyl side chain of the aralkyl group may instead or in addition besubstituted with at least one, and preferably no more than one, hydroxygroup. R⁶ is more preferably an aralkyl group in which the alkyl part isC₁ -C₃ and the aryl part is a phenyl group, which may be substituted orunsubstituted, where the substituent is at least one atom or groupselected from the group consisting of: straight and branched chain alkylgroups containing from 1 to 3 carbon atoms; halogen atoms; and alkoxygroups containing from 1 to 3 carbon atoms. Examples of such substitutedgroups include: aralkyl groups substituted with a straight or branchedchain alkyl group containing from 1 to 5 carbon atoms, such as the4-methylbenzyl, 4-ethylbenzyl and 3-propylbenzyl groups;halo-substituted aralkyl groups, such as the 2-chlorobenzyl,4-chlorobenzyl, 2,6-dichlorobenzyl, 2-fluorobenzyl, 2-fluorophenethyl,2-bromobenzyl and 4-bromophenethyl groups; and aralkyl groupssubstituted with a straight or branched chain alkoxy group containingfrom 1 to 5 carbon atoms, such as the 4-methoxybenzyl,3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 4-ethoxybenzyl,4-propoxybenzyl, 4-methoxyphenethyl and 3,4-dimethoxyphenethyl groups.

In the above exemplification of the groups which may be represented byR⁴, R⁵ and R⁶, the examples of groups referred to apply also to thosegroups represented by R^(4'), R^(5'), R^(6'), R^(4") and R^(5"), so faras the case may allow.

In general, where substituents are referred to above, there is norestriction on the number of such substituents, except, as specificallyexplained in relation to substituents on aryl groups, those that mightarise as a result of the number of substitutable positions on the groupbearing the substituent(s), and possibly also steric constraints.Although the exact number of substituents permissible may, therefore,vary in a manner well known to those skilled in the art, as a generalrule, from 1 to 3 such substituents are preferred, except whereotherwise indicated herein.

The preferred compounds of formula (Ia) of the present invention arethose in which:

R¹ represents a hydrogen atom; a straight or branched chain alkyl groupcontaining from 1 to 5 carbon atoms; or a carbocyclic aryl groupcontaining from 6 to 10 carbon atoms, the aryl group being unsubstitutedor having at least one substituent selected from the group consisting ofsubstituents (a), defined and exemplified above;

R³ represents a straight or branched chain alkyl group containing from 1to 5 carbon atoms; or a cycloalkyl group containing from 3 to 7 carbonatoms;

R^(4') represents a hydrogen atom; a hydroxy group; or a straight orbranched chain alkyl group containing from 1 to 5 carbon atoms;

R^(5') represents a hydrogen atom; a hydroxy group; or a straight orbranched chain alkyl group containing from 1 to 5 carbon atoms;

R^(6') represents a hydrogen atom; a straight or branched chain alkylgroup containing from 1 to 15 carbon atoms; a substituted straight orbranched chain alkyl group containing from 1 to 5 carbon atoms andhaving at least one substituent selected from the group consisting ofsubstituents (b'), defined below; a cycloalkyl group containing from 3to 10 carbon atoms; an alkenyl group containing from 3 to 7 carbonatoms; a carbocyclic aryl group containing from 6 to 10 carbon atomswhich aryl group is unsubstituted or has at least one substituentselected from the group consisting of substituents (a), defined above;or an aralkyl group in which the alkyl part is C₁ -C₃ and the aryl partis a phenyl group which is unsubstituted or has at least one substituentselected from the group consisting of substituents (c), defined above;

substituents (b')

halogen atoms, hydroxy groups, mercapto groups, dialkylamino groups inwhich each alkyl group has from 1 to 5 carbon atoms and is unsubstitutedor has at least one hydroxy substituent, five- and six-memberedheterocyclic groups which are unsubstituted or have at least one C₁ -C₅alkyl substituent and which additionally contain 0, 1 or 2 nitrogenand/or oxygen atoms in the ring, phenoxy groups, alkoxy groupscontaining from 1 to 5 carbon atoms, benzoyl groups which areunsubstituted or have at least one substituent selected from the groupconsisting of substituents (d), defined above, benzoyloxy groups whichare unsubstituted or have at least one substituent selected from thegroup consisting of substituents (d), defined above, andheterocyclic-carbonyloxy groups in which the heterocyclic part has from5 to 6 ring atoms of which 1 or 2 are nitrogen hetero-atoms;

and pharmaceutically acceptable salts thereof.

The more preferred compounds of formula (Ia) of the present inventionare those in which:

R¹ represents a hydrogen atom, a C₁ -C₃ alkyl group, or a phenyl group,which is unsubstituted or has at least one substituent selected from thegroup consisting of substituents (a'), defined below;

R³ represents a C₁ -C₃ alkyl group or a cycloalkyl group containing from3 to 5 carbon atoms;

R^(4') represents a hydrogen atom, a hydroxy group or a C₁ -C₃ alkylgroup;

R^(5') represents a hydrogen atom, a hydroxy group or a C₁ -C₃ alkylgroup;

R^(6') represents a hydrogen atom; a C₁ -C₁₂ alkyl group; a C₁ -C₅ alkylgroup having at least one substituent selected from the group consistingof substituents (b"), defined below; an alkenyl group containing from 3to 5 carbon atoms; a cycloalkyl group containing from 5 to 8 carbonatoms; a phenyl group which is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (a'),defined below: or an aralkyl group in which the alkyl part is a C₁ -C₃alkyl group and the aryl part is a phenyl group which is unsubstitutedor has at least one substituent selected from the group consisting ofsubstituents (c'), defined below;

substituents (a')

C₁ -C₃ alkyl groups, halogen atoms, C₁ -C₃ alkoxy groups and sulfamonylgroups;

substituents (b")

hydroxy groups; dialkylamino groups in which each alkyl part is C₁ -C₅and is unsubstituted or has at least one hydroxy substituent;heterocyclic groups having from 5 to 6 ring atoms of which 1 is anitrogen atom through which the group is attached to the remainder ofthe molecule and 0, 1 or 2 are additional hetero-atoms selected from thegroup consisting of nitrogen and oxygen hetero-atoms, said group beingunsubstituted or having at least one C₁ -C₅ alkyl substituent; phenoxygroups; C₁ -C₃ alkoxy groups; benzoyloxy groups which are unsubstitutedor have at least one halogen and/or C₁ -C₃ alkoxy substituent; andheterocyclic-carbonyloxy groups in which the heterocyclic part has from5 to 6 ring atoms of which 1 or 2 are nitrogen hetero-atoms;

substituents (c')

C₁ -C₃ alkyl groups, halogen atoms and C₁ -C₃ alkoxy groups;

and pharmaceutically acceptable salts thereof.

Still more preferred compounds of formula (Ia) of the present inventionare those in which:

R¹ represents a hydrogen atom; a methyl group; a phenyl group which isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (a"), defined below;

R³ represents a methyl group or a cyclopropyl group;

R^(4') represents a hydrogen atom or a methyl group

R^(5') represents a hydrogen atom or a C₁ -C₃ alkyl group;

R^(6') represents a hydrogen atom; a C₁ -C₁₂ alkyl group; a C₁ -C₅ alkylgroup having at least one substituent selected from the group consistingof substituents (b"), defined above; an alkenyl group containing from 3to 5 carbon atoms; a cycloalkyl group containing from 5 to 8 carbonatoms; an unsubstituted phenyl group; a substituted phenyl group whichhas at least one substituent selected from the group consisting ofhalogen atoms and sulfamoyl groups; or an aralkyl group in which thealkyl part is a C₁ -C₃ alkyl group and the aryl part is a phenyl groupwhich is unsubstituted or has at least one substituent selected from thegroup consisting of substituents (c'), defined above;

substituents (a")

halogen atoms and C₁ -C₃ alkoxy groups;

and pharmaceutically acceptable salts thereof.

The most preferred compounds of formula (Ia) of the present inventionare those in which:

R¹ represents a hydrogen atom or a phenyl group which is unsubstitutedor has at least one substituent selected from the group consisting of C₁-C₃ alkoxy groups;

R³ represents a methyl or cyclopropyl group;

R^(4') represents a hydrogen atom;

R^(5') represents a hydrogen atom or a C₁ -C₃ alkyl group;

R^(6') represents a C₁ -C₁₂ alkyl group; a C₁ -C₅ alkyl group having atleast one substituent selected from the group consisting of substituents(b"'), defined below; an alkenyl group containing from 3 to 5 carbonatoms; a cycloalkyl group containing from 5 to 8 carbon atoms; or anaralkyl group in which the alkyl part is a C₁ -C₃ alkyl group and thearyl part is a phenyl group which is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (c'),defined above;

substituents (b"')

hydroxy groups; heterocyclic groups having from 5 to 6 ring atoms ofwhich 1 is a nitrogen atom through which the group is attached to theremainder of the molecule and 0, 1 or 2 are additional hetero-atomsselected from the group consisting of nitrogen and oxygen hetero-atoms;phenoxy groups; benzoyloxy groups which are unsubstituted or have atleast one substituent selected from the group consisting of halogenatoms and

C₁ -C₃ alkoxy groups; and heterocyclic-carbonyloxy groups in which theheterocyclic part has from 5 to 6 ring atoms of which 1 or 2 arenitrogen hetero-atoms;

and pharmaceutically acceptable salts thereof.

The preferred compounds of formula (Ib) of the present invention arethose in which:

R¹ represents a hydrogen atom or a phenyl group;

R² represents a hydrogen, bromine or chlorine atom;

R³ represents a methyl group;

R^(4") represents a hydrogen atom, or, but only when the dotted linerepresents a double bond, a bromine atom;

R^(5") represents a hydrogen atom, or, but only when the dotted linerepresents a double bond, a bromine atom; and

R⁶ represents a C₁ -C₁₂ alkyl group, a C₁ -C₄ alkyl group having atleast one substituent selected from the group consisting of substituents(b^(iv)), defined below, an allyl group, a propargyl group, a C₅ -C₇cycloalkyl group, a phenyl group, or a phenylalkyl group in which thealkyl part is C₁ -C₃ and is unsubstituted and the phenyl part isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (c"), defined below;

substituents (b^(iv))

halogen atoms, hydroxy groups, mercapto groups, heterocyclic groupshaving from 5 to 6 ring atoms of which 1 is a nitrogen atom throughwhich the group is attached to the remainder of the molecule and 0, 1 or2 are additional hetero-atoms selected from the group consisting ofnitrogen and oxygen hetero-atoms, said heterocyclic group beingunsubstituted or having at east one C₁ -C₃ alkyl substituent, benzoyloxygroups and substituted benzoyloxy groups having at least one methoxysubstituent;

substituents (c")

methyl groups, chlorine atoms, fluorine atoms and methoxy groups;

and pharmaceutically acceptable salts thereof.

The more preferred compounds of formula (Ib) of the present inventionare those in which:

R¹ represents a hydrogen atom or a phenyl group;

R² represents a hydrogen, bromine or chlorine atom;

R³ represents a methyl group;

R^(4") represents a hydrogen atom;

R^(5") represents a hydrogen atom, or, but only when the dotted linerepresents a double bond, a bromine atom; and

R⁶ represents a C₂ -C₄ alkyl group, a cycloheptyl group or a phenylalkylgroup in which the alkyl part is C₁ -C₃ and is unsubstituted and thephenyl part is unsubstituted or has at least one substituent selectedfrom the group consisting of methyl groups and methoxy groups;

and pharmaceutically acceptable salts thereof.

The compounds of the present invention necessarily contain basic groupsand can, therefore, form acid addition salts. The nature of such saltsand of the acids employed to form them is not critical to the invention,provided that, where the compound is intended for use therapeutically,the salt is pharmaceutically acceptable, which, as is well known, meansthat it does not have a lower (or significantly lower) activity or ahigher (or significantly higher) toxicity than the free base. However,where the compound is intended for other uses, e.g. as an intermediatein the preparation of other compounds, even this limitation does notapply.

Examples of acids which can form such salts include: inorganic acids,such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoricacid, sulfuric acid or nitric acid; organic sulfonic acids, such asmethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid orp-toluenesulfonic acid; and organic carboxylic acids, such as oxalicacid, tartaric acid, citric acid, maleic acid, malonic acid, succinicacid, acetic acid, benzoic acid, mandelic acid, ascorbic acid, lacticacid, gluconic acid and malic acid.

Examples of the known class of compounds which may be used in thepresent invention are those compounds of formula (Ia) in which R¹, R³,R^(4'), R^(5') and R^(6') are as defined in the following Table 1. InCompound No. 43, the compound is a quaternary ammonium salt, in whichthe methyl iodide shown in addition to the t-butyl group in the columnfor R^(6') is the quaternizing compound. Examples of the new compoundsof the invention are those compounds of formula (I-2) and (I-3), shownbelow, in which R¹, R², R³, R^(4'), R^(5") and R⁶ are as defined inTables 2 and 3, respectively. In these Tables, the followingabbreviations are used:

    ______________________________________                                        All            allyl                                                          Boz            benzoyl                                                        Bu             butyl                                                           .sub.-iBu     isobutyl                                                        .sub.-sBu     sec-butyl                                                       .sub.-tBu     t-butyl                                                        Bz             benzyl                                                         Dc             decyl                                                          Ddc            dodecyl                                                        Et             ethyl                                                          Hp             heptyl                                                          -cHp          cycloheptyl                                                    Hx             hexyl                                                           -cHx          cyclohexyl                                                     Me             methyl                                                         Mor            morpholino                                                     Nic            nicotinoyl                                                     Oc             octyl                                                          Ph             phenyl                                                         Pip            piperidyl                                                      Piz            piperazinyl                                                    Pn             pentyl                                                          -cPn          cyclopentyl                                                     .sub.-iPn     isopentyl                                                       .sub.-tPn     t-pentyl                                                       Pr             propyl                                                          -cPr          cyclopropyl                                                     .sub.-iPr     isopropyl                                                      Prg            propargyl (= 2-propynyl)                                       Pyrd           pyrrolidinyl                                                   Sam            sulfamoyl                                                      ______________________________________                                         ##STR6##

                  TABLE 1                                                         ______________________________________                                        Cpd                                                                           No.  R.sup.1     R.sup.3                                                                              R.sup.4'                                                                           R.sup.5'                                                                           R.sup.6'                                    ______________________________________                                        1-1  H           Me     H    H    H                                           1-2  H           Me     H    H    Me                                          1-3  4-MeOPh     Me     H    H    Me                                          1-4  H           Me     H    H    Et                                          1-5  H           Me     H    H    Pr                                          1-6  H           Me     H    H     .sub.-iPr                                  1-7  Ph          Me     H    H     .sub.-iPr                                  1-8  4-ClPh      Me     H    H     .sub.-iPr                                  1-9  4-MeOPh     Me     H    H     .sub.-iPr                                  1-10 H           Me     H    Me    .sub.-iPr                                  1-11 H           Me     H    Et    .sub.-iPr                                  1-12 H            -cPr  H    H     .sub.-iPr                                  1-13 H           Me     H    H    Bu                                          1-14 Ph          Me     H    H    Bu                                          1-15 H           Me     H    Me   Bu                                          1-16 H           Me     H    Et   Bu                                          1-17 H           Me     H    H     .sub.-sBu                                  1-18 H           Me     H    H     .sub.-iBu                                  1-19 H           Me     H    H      .sub.-tBu                                 1-20 Me          Me     H    H     .sub.-tBu                                  1-21 Ph          Me     H    H     .sub.-tBu                                  1-22 4-ClPh      Me     H    H     .sub.-tBu                                  1-23 4-MeOPh     Me     H    H     .sub.-tBu                                  1-24 3,4,5-triMeOPh                                                                            Me     H    H     .sub.-tBu                                  1-25 H           Me     Me   H     .sub.-tBu                                  1-26 H           Me     H    Me    .sub.-tBu                                  1-27 H           Me     H    Et    .sub.-tBu                                  1-28 H            -cPr  H    H     .sub.-tBu                                  1-29 H           Me     H    H    Pn                                          1-30 H           Me     H    H     .sub.-iPn                                  1-31 H           Me     H    H     .sub.-tPn                                  1-32 H            -cPr  H    H     .sub.-tPn                                  1-33 H           Me     H    H    Hx                                          1-34 H           Me     H    H    1,3-diMeBu                                  1-35 H           Me     H    H    Hp                                          1-36 H           Me     H    H    1,1,3,3-tetraMeBu                           1-37 H           Me     H    H    Dc                                          1-38 H           Me     H    H    Ddc                                         1-39 H           Me     H    H    All                                         1-40 H           Me     H    H     -cHx                                       1-41 H           Me     H    H     -cHp                                       1-42 H           Me     H    H     -cOc                                       1-43 H           Me     H    H     .sub.-tBu.MeI                              1-44 H           Me     H    H    Ph                                          1-45 H           Me     H    H    2,6-diClPh                                  1-46 H           Me     H    H    4-SamPh                                     1-47 H           Me     H    H    Bz                                          1-48 H           Me     H    H    4-MeBz                                      1-49 H           Me     H    H    4-MeOBz                                     1-50 H           Me     H    Me   4-MeOBz                                     1-51 H           Me     H    H    3,4-diMeOBz                                 1-52 H           Me     H    H    3,4,5-triMeOBz                              1-53 H           Me     H    H    2-ClBz                                      1-54 H           Me     H    H    4-ClBz                                      1-55 3,4,5-triMeOPh                                                                            Me     H    H    2-ClBz                                      1-56 H           Me     H    H    2-ClBz                                      1-57 H            -cPr  H    H    2-ClBz                                      1-58 H           Me     H    H    2-FBz                                       1-59 Ph          Me     H    H    2-FBz                                       1-60 H           Me     H    Me   2-FBz                                       1-61 H           Me     H    Et   2-FBz                                       1-62 H           Me     H    H    1-PhEt                                      1-63 H           Me     H    H    2-PhEt                                      1-64 H            -cPr  H    H    2-PhEt                                      1-65 H           Me     H    H    2-(3,4-diMeOPh)Et                           1-66 H           Me     H    H    2-HO-1-Me-2-PhEt                            1-67 Me          Me     H    H    2-ClBz                                      1-68 H           Me     H    H    2-(Et.sub.2 N)Et                            1-69 H           Me     H    H    2-(1-Pyrd)Et                                1-70 H           Me     H    H    2-(1-Pip)Et                                 1-71 H           Me     H    H    2-MorEt                                     1-72 H           Me     H    H    2-(4-Me-1-Piz)Et                            1-73 H           Me     H    H    3-(Me.sub.2 N)Pr                            1-74 H           Me     H    H    3-(Bu.sub.2 N)Pr                            1-75 H           Me     H    H    3-[(2-HOEt).sub.2 N]Pr                      1-76 H           Me     H    H    3-(1-Pyrd)Pr                                1-77 Me          Me     H    H    3-(1-Pyrd)Pr                                1-78 Ph          Me     H    H    3-(1-Pyrd)Pr                                1-79 4-ClPh      Me     H    H    3-(1-Pyrd)Pr                                1-80 4-MeOPh     Me     H    H    3-(1-Pyrd)Pr                                1-81 H           Me     H    H    3-(1-Pip)Pr                                 1-82 H           Me     H    H    3-MorPr                                     1-83 H           Me     H    H    2-HOEt                                      1-84 H           Me     H    H    3-HOPr                                      1-85 H           Me     H    H    2-HOPr                                      1-86 H           Me     H    H    2-HO-1,1,-diMeEt                            1-87 H           Me     H    H    2,3-diHOPr                                  1-88 H           Me     H    H    2-(2-HOEtO)Et                               1-89 H           Me     H    H    1-Me-2-PhOEt                                1-90 H           Me     H    H    2-BozEt                                     1-91 H           Me     H    H    2-HSEt                                      1-92 H           Me     H    H    2-ClEt                                      1-93 H           Me     H    H    3-ClPr                                      1-94 H           Me     H    H    2-(3,4,5-                                                                     triMeOBozO)Et                               1-95 H           Me     H    H    2-NicOEt                                    1-96 H           Me     H    H    3-(3,4,5-                                                                     triMeOBozO)Pr                               1-97 H           Me     H    H    3-NicOPr                                    1-98 H           Me     OH   OH    .sub.-tBu                                  1-99 H           Me     OH   H     .sub.-tBu                                  1-100                                                                              H           Me     H    ═O                                                                              .sub.-tBu                                  1-101                                                                              H           Me     H    OH    .sub.-tBu                                  ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Cpd                                                                           No.  R.sup.1                                                                             R.sup.2                                                                             R.sup.3                                                                            R.sup.4"                                                                            R.sup.5"                                                                            R.sup.6                                     ______________________________________                                        2-1  H     H     Me   H     H      .sub.-tBu                                  2-2  H     H     Me   H     H     Bz                                          2-3  H     Br    Me   H     H     Bz                                          2-4  H     Br    Me   H     H     Et                                          2-5  H     Br    Me   H     H     3-MorPr                                     2-6  H     Br    Me   H     H     2-HOEt                                      2-7  H     Br    Me   H     H      -o-ClBz                                    2-8  H     Br    Me   H     H     2-(3,4-diMeOPh)Et                           2-9  H     Cl    Me   H     H      .sub.-tBu                                  2-10 H     Br    Me   H     H       -p-MeBz                                   2-11 H     Br    Me   H     H      -p-MeOBz                                   2-12 H     Br    Me   H     H     3-HOPr                                      2-13 H     Cl    Me   H     H     4-(1-Pyrd)Bu                                2-14 H     Br    Me   H     H     4-(1-Pyrd)Bu                                2-15 H     H     Me   H     H     α,α-diMeBz                      2-16 H     Br    Me   H     H     Pr                                          2-17 H     Br    Me   H     H     Bu                                          2-18 H     Br    Me   H     H     Ddc                                         2-19 H     Br    Me   H     H      -cPn                                       2-20 H     Br    Me   H     H      -cHp                                       2-21 H     Br    Me   H     H     2-(3,4,5-triMeOBozO)Et                      2-22 Ph    H     Me   H     H     Et                                          2-23 Ph    Br    Me   H     H     Et                                          2-24 H     Br    Me   H     H     Prg                                         2-25 H     Cl    Me   H     H     Prg                                         ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Cpd                                                                           No.  R.sup.1                                                                             R.sup.2                                                                             R.sup.3                                                                            R.sup.4"                                                                            R.sup.5"                                                                            R.sup.6                                     ______________________________________                                        3-1  H     Br    Me   H     H     Me                                          3-2  H     Br    Me   H     Br    Me                                          3-3  H     Br    Me   H     H     Bu                                          3-4  H     Br    Me   H     H     Ddc                                         3-5  H     Br    Me   H     Br    Et                                          3-6  H     Br     -cPr                                                                              H     H     Bz                                          3-7  H     Br     -cPr                                                                              H     H     Et                                          3-8  H     Br     -cPr                                                                              H     H     Pr                                          3-9  H     Br     -cPr                                                                              H     H     Bu                                          3-10 H     Br    Me   Br    H      .sub.-tBu                                  3-11 H     H     Me   H     H     Et                                          3-12 H     Cl    Me   H     H     Et                                          3-13 H     Br    Et   H     H     Bz                                          3-14 H     Cl    Pr   H     H     Bz                                          3-15 H     Cl     -cPn                                                                              H     H     Bz                                          3-16 H     Br     -cPn                                                                              H     H     Bz                                          3-17 H     Br     -cPn                                                                              H     H     Et                                          3-18 H     Br    Me   H     H       .sub.-iPr                                 3-19 H     Br    Me   H     H      -cPn                                       3-20 H     Br    Me   H     H      -cHx                                       3-21 H     Br    Me   H     H      -cHp                                       3-22 H     Br    Me   H     H     2-MorEt                                     2-23 H     Br    Me   H     H     2-(3,4-diMeOPh)Et                           3-24 H     Br    Me   H     H     All                                         3-25 H     Br    Me   H     H      -o-FBz                                     3-26 H     Br    Me   H     H     2-HOEt                                      3-27 H     Br    Me   H     H     2-(3,4,5-triMeOBozO)Et                      3-28 Ph    H     Me   H     H     Et                                          3-29 Ph    Br    Me   H     H     Et                                          3-30 H     Br    Me   H     H      .sub.-tBu                                  ______________________________________                                    

Of the compounds listed above, the following are preferred, that is tosay Compounds No. 1-3. 1-5, 1-13, 1-18, 1-19, 1-24, 1-28, 1-29, 1-30,1-31, 1-33, 1-34, 1-35, 1-37, 1-38, 1-39, 1-41, 1-42, 1-48, 1-49, 1-53,1-54, 1-56, 1-62, 1-63, 1-65, 1-82, 1-86, 1-89, 1-94, 1-96, 1-97, 1-98,1-99, 2-2, 2-4, 2-9, 2-10, 2-11, 2-15, 2-20, 2-22, 3-5 and 3-28, and thefollowing are the following are more preferred, that is to say CompoundsNo. 1-3, 1-13, 1-18, 1-19, 1-24, 1-28, 1-29, 1-30, 1-31, 1-33, 1-34,1-35, 1-37, 1-38, 1-39, 1-41, 1-42, 1-48, 1-49, 1-53, 1-54, 1-56, 1-62,1-63, 1-82, 1-89, 1-97, 1-98, 1-99, 2-2, 2-4, 2-11, 2-15, 2-22, 3-5 and3-28.

The following are the most preferred compounds:

1-13.8-butyl-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine;

1-19.8-t-butyl-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine;

1-28.8-t-butyl-5-cyclopropyl-7,8-dihydro-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine;

1-31.7,8-dihydro-5-methyl-8-t-pentyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine;

1-35.8-heptyl-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine;

1-41.8-cycloheptyl-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine;

1-42.8-cyclooctyl-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine;

1-48.7,8-dihydro-5-methyl-8-(4-methylbenzyl)-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine;

1-49.7,8-dihydro-8-(4-methoxybenzyl)-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine;

1-54.8-(4-chlorobenzyl)-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine;

1-62.7,8-dihydro-5-methyl-8-(α-methylbenzyl)-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine;

1-89.7,8-dihydro-5-methyl-8-(1-methyl-2-phenoxyethyl)6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine;

2-2.8-benzyl-7,8-dihydro-5-methyl-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine;

and pharmaceutically acceptable salts thereof.

Of the above compounds, only Compound No. 2-2 is claimed per se.

The compounds of the present invention can also form quaternary ammoniumsalts with suitable other compounds, especially alkyl halides in whichthe alkyl group contains from 1 to 4 carbon atoms, for example methylchloride, methyl iodide, methyl bromide, ethyl chloride, ethyl iodide,ethyl bromide, propyl iodide and butyl iodide. They may be prepared bywell known methods, e.g. as illustrated for the preparation of themethyl iodide salt in the Journal of Medicinal Chemistry, 23, 927-937(1980).

All of the compounds of formula (Ia) shown above are known compounds andtheir properties and preparation are described in Japanese PatentApplication Kokai No. Sho 51-141896, Japanese Patent Application KokaiNo. Sho 52-116497, Japanese Patent Application Kokai No. Sho 53-53697,U.S. Pat. No. 4 007 189 and the Journal of Medicinal Chemistry, 23,927-937 (1980), the disclosures whereof are incorporated herein byreference.

The new compounds of the present invention can be prepared by a varietyof methods well known per se, but, in general terms, they may beprepared by the following steps:

(a) reacting a compound of formula (Iv): ##STR7## (in which R¹, R² andR³ are as defined above) with a primary amine of formula R⁶ NH₂, to givea compound of formula (V): ##STR8## (in which R¹, R², R³ and R⁶ are asdefined above), and, if required,

(b) dehydrogenating said compound of formula (V), to prepare a compoundof formula (VI): ##STR9## (in which R¹, R², R³ and R⁶ are as defined andthe dotted line represents a carbon-carbon double bond), and, ifrequired,

(c) halogenating said compound of formula (VI) to prepare a compound offormula (VII): ##STR10## (in which R¹, R², R³ and R⁶ are as definedabove, the dotted line represents a carbon-carbon double bond, and oneof R^(5") and R^(6") represents a halogen atom and the other of R^(5")and R^(6") represents a halogen atom or a hydrogen atom), and ifrequired, salifying the product.

In more detail, the new compounds of the present invention can beprepared as follows:

Step (a)

This consists of a ring closure reaction by condensation of a compoundof formula (VIII): ##STR11## (wherein R¹ is as defined above) with acompound of formula (IX): ##STR12## (wherein R³ is as defined above) toproduce a compound of formula (X): ##STR13## (wherein R¹ and R³ are asdefined above).

The reaction is preferably effected in a solvent. There is no particularrestriction on the nature of the solvent to be employed, provided thatit has no adverse effect on the reaction or on the reagents involved.Examples of suitable solvents include: ethers, such as tetrahydrofuranand dioxane; aromatic hydrocarbons, such as benzene, toluene and xylene;alcohols, such as methanol and ethanol; amides, especially fatty acidamides, such as dimethylformamide and dimethylacetamide. Aromatichydrocarbons and amides are preferred, and amides are most preferred.The amount of the lactone of formula (IX) to be employed is preferablyat least equimolar and more preferably from 1 to 2 times equimolar, withrespect to the compound of formula (VIII). The reaction can take placeover a wide range of temperatures, and the precise reaction temperatureis not critical to the invention. In general, we find it convenient tocarry out the reaction at a temperature from about 50° C. to the boilingpoint of the solvent employed. The time required for the reaction mayalso vary widely, depending on many factors, notably the reactiontemperature and the nature of the reagents. However, provided that thereaction is effected under the preferred conditions outlined above, aperiod of from 10 minutes to 30 hours will usually suffice.

Step (b)

This step consists of the reaction of the compound of formula (X)obtained as described above with phosphorus oxychloride to produce acompound of formula (XI). The reaction can be carried out in the absenceor presence of a solvent. ##STR14##

There is no particular restriction on the nature of the solvent whichmay be employed, provided that it has no adverse effect on the reactionor on the reagents involved. Examples of suitable solvents include:ethers, such as tetrahydrofuran or dioxane; aromatic hydrocarbons, suchas benzene, toluene or xylene; and halogenated hydrocarbons, especiallyhalogenated aliphatic hydrocarbons such as methylene chloride,chloroform or carbon tetrachloride. It is usually preferred to conductthe reaction in the absence of a solvent. The reaction can take placeover a wide range of temperatures, and the precise reaction temperatureis not critical to the invention. In general, we find it convenient tocarry out the reaction at a temperature from about 50° C. to the boilingpoint of the solvent employed. The time required for the reaction mayalso vary widely, depending on many factors, notably the reactiontemperature and the nature of the reagents. However, provided that thereaction is effected under the preferred conditions outlined above, aperiod of from about 10 minutes to 10 hours will usually suffice.

Step (c)

A compound of formula (XII) can be prepared by treating the compound offormula (XI) obtained as described above with a halogenating agent, suchas N-chlorosuccinimide or N-bromosuccinimide in the presence of an inertsolvent. ##STR15## (in which R¹ and R³ are as defined above, and R^(2')represents a halogen atom).

There is no particular restriction on the nature of the solvent to beemployed, provided that it has no adverse effect on the reaction or onthe reagents involved. Examples of suitable solvents include: ethers,such as tetrahydrofuran or dioxane; aromatic hydrocarbons, such asbenzene, toluene or xylene; and halogenated hydrocarbons, especiallyhalogenated aliphatic hydrocarbons, such as methylene chloride,chloroform or carbon tetrachloride. The reaction can take place over awide range of temperatures, and the precise reaction temperature is notcritical to the invention. In general, we find it convenient to carryout the reaction at a temperature from about 0° C. to the boiling pointof the solvent employed. The time required for the reaction may alsovary widely, depending on many factors, notably the reaction temperatureand the nature of the reagents. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of fromabout 10 minutes to 10 hours will usually suffice.

Step (d)

A compound of formula (V) can be prepared by treating the compound offormula (XI) or (XII) with a primary amine of formula R⁶ NH₂ in an inertsolvent and, if necessary, in the presence of a base. ##STR16## (inwhich R¹, R², R³ and R⁶ are as defined above).

The choice of the primary amine of formula R⁶ NH₂ will, of course dependsolely upon the nature of the group R⁶ which it is desired to introduceinto the compound.

The nature of the base which may be employed in this reaction is notcritical, provided that it does not adversely affect any other part ofthe molecule of the compound of formula (XI) or (XII), and examplesinclude: organic bases such as triethylamine, pyridine or1,8-diazabicyclo[5.4.0]-7-undecene (DBU); and alkali metal carbonatesand bicarbonates, such as sodium carbonate, potassium carbonate andsodium bicarbonate.

There is no particular restriction on the nature of the solvent to beemployed, provided that it has no adverse effect on the reaction or onthe reagents involved. Examples of suitable solvents include: ethers,such as tetrahydrofuran or dioxane; aromatic hydrocarbons, such asbenzene, toluene or xylene; halogenated hydrocarbons, especiallyhalogenated aliphatic hydrocarbons, such as methylene chloride,chloroform or carbon tetrachloride; alcohols, such as methanol, ethanolor isopropanol; and amides, especially fatty acid amides, such asdimethylformamide or dimethylacetamide. Alcohols are preferablyemployed. The amount of the base to be employed may vary depending uponthe nature of the primary amine employed but is usually and preferablyfrom equimolar to 3 times equimolar, with respect to the compound offormula (XI) or (XII). The amount of the primary amine to be employed ispreferably from equimolar to 10 times equimolar, also with respect tothe compound of formula (XI) or (XII). The reaction can take place overa wide range of temperatures, and the precise reaction temperature isnot critical to the invention. In general, we find it convenient tocarry out the reaction at a temperature from about 20° C. to the boilingpoint of the solvent employed. The time required for the reaction mayalso vary widely, depending on many factors, notably the reactiontemperature and the nature of the reagents. However, provided that thereaction is effected under the preferred conditions outlined above, aperiod of from about 10 minutes to 30 hours will usually suffice.

Step (e)

The compound of formula (V) obtained as described above can be convertedto a compound of formula (VI) by dehydrogenation. ##STR17## (in whichR¹, R², R³ and R⁶ are as defined above, and the dotted line represents acarbon-carbon double bond).

Conventional dehydrogenation agents may be used in this reaction, forexample, benzoyl peroxide, metal oxides such as manganese dioxide, anddehydrogenation catalysts, such as palladium-on-carbon.

The reaction is normally and preferably effected in the presence of asolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved. Examples of suitable solvents include:ethers, such as tetrahydrofuran or dioxane; aromatic hydrocarbons, suchas benzene, toluene or xylene; and halogenated hydrocarbons, especiallyhalogenated aliphatic hydrocarbons, such as methylene chloride,chloroform or carbon tetrachloride.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature from about 0° C. to the boiling point of the solventemployed. The time required for the reaction may also vary widely,depending on many factors, notably the reaction temperature and thenature of the reagents. However, provided that the reaction is effectedunder the preferred conditions outlined above, a period of from about 10minutes to 30 hours will usually suffice.

Step (f)

A compound of formula (VII) can be prepared by treating the compound(VI) obtained as described above with a halogenating agent, such asN-chlorosuccinimide or N-bromosuccinimide in the presence of an inertsolvent. ##STR18## (in which R¹, R², R³ and R⁶ are as defined above, thedotted line represents a carbon-carbon double bond, and one of R^(5')and R^(6') represents a halogen atom and the other of R^(5') and R^(6')represents a halogen atom or a hydrogen atom),

There is no particular restriction on the nature of the solvent to beemployed, provided that it has no adverse effect on the reaction or onthe reagents involved. Examples of suitable solvents include ethers,such as tetrahydrofuran or dioxane; aromatic hydrocarbons, such asbenzene, toluene or xylene; and halogenated hydrocarbons, especiallyhalogenated aliphatic hydrocarbons, such as methylene chloride,chloroform or carbon tetrachloride. Halogenated hydrocarbons arepreferred. The reaction can take place over a wide range oftemperatures, and the precise reaction temperature is not critical tothe invention. In general, we find it convenient to carry out thereaction at a temperature from about 0° C. to the boiling point of thesolvent employed. The time required for the reaction may also varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of fromabout 10 minutes to 10 hours will usually suffice.

The desired product obtained as described in any of the above steps maybe isolated and purified by conventional means, for example bysolvent-extraction, dilution, recrystallization, or the variouschromatography techniques, notably column chromatography and preparativethin layer chromatography.

The basic compounds of formula (I) may easily be converted to thecorresponding acid addition salts by treatment with a suitablepharmaceutically acceptable acid, Suitable acids include: inorganicacids such as hydrochloric acid, sulfuric acid, phosphoric acid orhydrobromic acid; and organic acids such as acetic acid, oxalic acid,succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid,citric acid, malonic acid, methanesulfonic acid or benzoic acid.

BIOLOGICAL ACTIVITY Toxicity

All of the compounds of formula (I) employed in the present inventionhave shown low toxicity and high safety, with limited side effects. Theacute toxicity (LD₅₀) in rats receiving8-t-butyl-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine(Compound No. 1-19) by subcutaneous injection was not less than 100mg/kg. The acute toxicity (LD₅₀) in mice receiving8-(4-chlorobenzyl)-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazaolo[1,5-a]pyrimidine(Compound No. 1-54),8-(4-methoxybenzyl)-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine(Compound No. 1-49),8-(4-methylbenzyl)-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine(Compound No. 1-48) and8-benzyl-7,8-dihydro-5-methyl-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine(Compound No. 2-2) by intraperitoneal injection was not less than 300mg/kg in each case.

The compounds of the present invention may be administered in variousforms, as is conventional in the art. For example, they may beadministered orally in the form of tablets, capsules, granules, powders,syrups or the like or parenterally in the form of injections, drops orsuppositories. The dose may vary depending upon the symptoms, age andbody weight of the patient, and the nature and severity of the cachexiato be relieved, but, in general, the compounds of the invention may beadministered orally in a daily dose of from about 10 to 1,000 mg foradults, either as a single dose or as divided doses, or parenterally ina single dose of from 10 to 500 mg by hypodermic, intramuscular orintravenous injection.

The enhancement index employed herein is calculated as follows:

Induction, suppression and assay of the lipoprotein lipase are carriedout according to the methods reported by Beutler et al. [J. Immunol.,135, 3972-2977(1985)]. The differentiated adipocytes (3T3-L1) areincubated for 18 hours in the presence of a 2% (v/v) dispersion of serumtaken from rabbits, to which the endotoxin had previously beenintravenously administered. The serum obtained is named TNS. The enzymeactivity of the adipocytes is determined after the incubation. Theactivity so determined corresponds to 5-15% of that activity which isdetermined after incubation in the presence of the serum taken fromrabbits which had not been administered the endotoxin.

When the compounds employed in this invention are added in an amount offrom 0.1 to 100 microgram/ml to the adipocyte culture and the culture isincubated for 18 hours in the presence of 2% of TNS, the enzyme activityis enhanced and is higher than the activity determined in the absence ofthe compound.

The enhancement index of the lipoprotein lipase=A/B, where:

A: Heparin releasable lipoprotein lipase activity of the adipocyte after18 hours incubation in the presence of TNS and the compounds tested.

B: Heparin releasable lipoprotein lipase activity of the adipocyte after18 hours incubation in the presence of TNS and in the absence of thecompounds.

The enhancement index of each compound is calculated at theconcentration to show the highest efficacy.

TNS is prepared according to the methods reported by Ostrove et al. [J.M. Ostrove et al.; proceeding of the Society for Experimental Biologyand Medicine, 160, 354-358(1979)]. Forty mg per head of lyophilizedhypodermic BCG vaccine (Japan BCG Ind., Japan) are injected into themarginal ear vein of female New Zealand white rabbits. Two weeks later,these rabbits are injected with 10 μg per head of the lipopolysaccharide(derived from E. coli 0127:B8, purchased from Difco Lab., USA) via theear vein, and the animals are bled 1.5-2 hours later after thechallenge. The blood obtained is incubated for 2 hours at 37° C. toallow clotting, and then centrifuged at 3,000 rpm for 10 minutes toobtain a serum without debris. The serum obtained is incubated at 56° C.for 30 minutes and is then sterilized by filtration through a 0.22 μmMillex-GS filter (Millipore Co. USA). The filtrate obtained is calledTNS.

The activity of the compounds of the present invention is illustrated bythe following experiments.

EXPERIMENT 1 Restoration of lipoprotein lipase in cultured adipocytes

The induction, suppression and determination of lipoprotein lipase werecarried out according to the methods reported by Beutler et al. asdescribed above [J. Immunol., 135, 3972-3977(1985)]. The fact that therestoration of lipolytic activity by the compounds of the presentinvention is due to the enhancement of the lipoprotein lipase, wasascertained as follows.

It is known that 1.0M of NaCl added to the reaction mixture for assayinhibits the activity of the lipoprotein lipase but does not inhibitboth hepatic triglyceride lipase [A. Bensadoun et al.; J. Biol. Chem.,249, 2220-2227(1974), J. C. LaRosa et al.; J. Lipid Res., 13,356-363(1972)]. The lipase activity of adipocytes incubated with thecompounds of the present invention was clearly detected in the reactionmixture containing 0.1 M NaCl, but not in the reaction mixturecontaining 1.0 M NaCl.

In addition, the lipase activity of the adipocytes (3T3-L1) incubatedwith the compounds of the present invention was not affected by 500 μMof chloropromazine, a specific inhibitor for the lysosomal lipase [G. L.Jansen et al.; J. Biol. Chem., 255, 11141-11148(1980)]. Accordingly, itis concluded that the lipolytic activity restored by the compounds isdue to lipoprotein lipase, when the activity is suppressed by TNS.

The remarkable restoration of the lipoprotein lipase by the compounds inthe invention, is shown in Table 4.

The compounds of the present invention are regarded as particularlyuseful as they each have an enhancement index of at least 2.

                  TABLE 4                                                         ______________________________________                                        Compound    Dosage   Enhancement of lipoprotein                               No.         (μg/ml)                                                                             lipase                                                   ______________________________________                                        1-3         10       3.0                                                      1-5         100      4.7                                                      1-13        10       2.5                                                      1-18        10       2.2                                                      1-19        10       8.5                                                      1-24        1.0      2.0                                                      1-28        10       9.5                                                      1-29        10       5.2                                                      1-30        10       10                                                       1-31        10       2.8                                                      1-33        10       5.6                                                      1-34        10       8.5                                                      1-35        10       6.9                                                      1-37        10       4.9                                                      1-38        10       10                                                       1-39        1.0      6.1                                                      1-41        10       10                                                       1-42        10       27                                                       1-48        10       12                                                       1-49        10       12                                                       1-53        10       3.0                                                      1-54        10       9.8                                                      1-56        10       4.0                                                      1-62        10       8.0                                                      1-63        10       6.0                                                      1-65        100      5.4                                                      1-82        10       9.0                                                      1-86        100      3.0                                                      1-89        10       8.1                                                      1-94        100      6.0                                                      1-96        100      19                                                       1-97        10       16                                                       1-98        10       3.2                                                      1-99        10       2.6                                                      2-2         10       11.2                                                     2-4         10       3.4                                                      2-9         1.0      2.0                                                      2-10        1.0      2.0                                                      2-11        0.1      3.7                                                      2-15        1.0      4.0                                                      2-20        10       2.7                                                      2-22        10       3.7                                                      3-5         1.0      4.8                                                      3-28        1.0      3.7                                                      ______________________________________                                    

EXPERIMENT 2 The enhancement of lipoprotein lipase activity in mice

Female mice (Balb/c, 10 weeks old, n=6, i.e. the number in each testgroup was 6) were injected with 9 mg/kg of the test compound (CompoundNo. 1-19) via the tail vein. Twenty one hours later, the activities ofthe plasma lipoprotein lipase were determined according to Vlassara'smethod. [Horm. Metabol. Res., 18, 698-703(1986)].

Activities of the plasma lipoprotein lipase in control mice receivingphysiological saline were expressed as 100 and the relative value isshown in the following Table 5.

                  TABLE 5                                                         ______________________________________                                                 Group receiving                                                                           Group receiving the                                               saline (n = 6)                                                                            test compound (n = 6)                                    ______________________________________                                        Relative activity                                                                        100 ± 13.5*                                                                              120 ± 10.6* -of the lipoprotein                   lipase                                                                        ______________________________________                                         *mean ± standard deviation.                                           

A significant difference between the two groups was observed (p<0.05).

As indicated above the lipoprotein lipase activity was increased to 120%of that of the control, when the mice were administrated the testcompound (Compound No. 1-19).

EXPERIMENT 3 The effects on improving cachexia and increasing life-spanof tumor bearing mice

A mouse cachexia model was made by inoculating 6×10⁵ viable tumor cells,adenocarcinoma C-12G, subcutaneously into the right axillary region of aCSF₁ mouse (8-9 weeks old, female weighing 21-24 g, n=10). The viabletumor cells were counted under a microscope after staining them with0.4% of trypan blue (Sigma Co.).

The growth of this kind of tumor, inoculated subcutaneously, causes amarked Weight loss (the weight losses of mice 16-17 days after tumorinoculation were (4.0-4.5 g), piloerection and depression of emotion andfinally death.

Compound No. 1-19 (hereafter called the test compound) was suspended insaline containing 0.5% CMC (carboxymethyl cellulose) at a concentrationof 4 mg/ml. The suspension was administrated orally to mice on days 1-4,7-11, 14-24 (20 times in total) after the tumor inoculation. The statusof the mice, such as weight loss. Piloerection, depression of emotionand increase in life-span, was observed.

On the other hand, for a control group of mice, saline solutioncontaining 0.5% of CMC was given orally. As a result of the oraladministration of the test compound, extensive improvements in weight,hair retention and emotion were observed in the mice. As shown in Table6 it was also found that the test compound produced an increase inlife-span (ILS) comparing with control mice.

                  TABLE 6                                                         ______________________________________                                                Dose     Median Survival                                                                            Increase in                                             (mg/kg/day)                                                                            time (day)   life-span (%)                                   ______________________________________                                        Control   --         28.0         --                                          Compound 1-19                                                                           40         40.5         45                                          ______________________________________                                         ##STR19##                                                                

In the above, the median survival times were measured in days.

The preparation of pharmaceutical compositions according to the presentinvention to illustrated in the following Formulations.

FORMULATION 1

    ______________________________________                                        Tablets                                                                       ______________________________________                                        (1)   8-t-Butyl-7,8-dihydro-5-methyl-                                                                        200    g                                             6 .sub.--H-pyrrolo[3,2-e][1,2,4]triazolo-                                     [1,5-a]pyrimidine (Compound No. 1-19)                                   (2)   Sodium pyrosulfate       5                                              (3)   Aerosil 200              5                                              (4)   Magnesium stearate       5                                              (5)   Lactose                  495                                            (6)   Cornstarch               154                                            (7)   Avicel                   123                                            (8)   HPC (L)                  10                                                                            997    g                                       ______________________________________                                    

A mixture of the powdered compounds 1 to 4 was added to granulesprepared from a mixture of the compounds 5 to 8, and the mixture wascompressed using a tablet machine to make a tablet containing 100 mg pertablet. The tablet may be sugar-coated, where necessary.

FORMULATION 2

    ______________________________________                                        Capsules                                                                      ______________________________________                                        (1)   8-t-Butyl-7,8-dihydro-5-methyl-                                                                        200    g                                             6 .sub.--H-pyrrolo[3,2-e][1,2,4]triazolo-                                     [1,5-a]pyrimidine (Compound No. 1-19)                                   (2)   Calcium phosphate, dibasic                                                                             200                                            (3)   Aluminum silicate        345                                            (4)   Crystalline Cellulose    250                                            (5)   Magnesium stearate       2                                                                             997    g                                       ______________________________________                                    

The above compounds 1 to 5 were mixed and pulverized, and then mixedwell through a sieve. Then, the mixture was made into capsulescontaining 200 mg per capsule by a conventional method.

The preparation of the new compounds of the present invention isillustrated by the following Examples.

EXAMPLE 1 6-(2-Hydroxyethyl)-5-methylpyrazolo[1,5-a]pyrimidin-7(4H)one

A solution of 49.86 g (0.6 mole) of 3-aminopyrazole and 84.56 g (0.66mole) of α-acetyl-γ-butyrolactone dissolved in 60 ml ofN,N-dimethylformamide was heated under reflux for 2 hours. At the end ofthis time, the reaction mixture was cooled to room temperature, afterwhich 100 ml of ethanol was added to it and the precipitated crystalswere collected by filtration. They were then washed with ethanol toafford 104.9 g (yield 90%) of the title compound as prisms, melting at225°-226° C.

¹ H-Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethylsulfoxide) δ ppm:

2.35 (3H, singlet);

2.42-2.82 (2H, multiplet);

3.20-3.70 (2H, multiplet);

4.58 (1H, triplet, J=6 Hz):

6.03 (1H, doublet, J=2 Hz);

7.81 (1H, doublet, J=2 Hz);

12.07 (1H, broad);

12.48 (1H, broad).

EXAMPLE 2

Following a similar procedure to that described in Example 1, 1.72 g(yield 63.9%) of6-(2-hydroxyethyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-(4H)-onewas prepared as a light brown powder, melting at 284° C. (withdecomposition).

EXAMPLE 3 7-Chloro-6-(2-chloroethyl)-5-methylpyrazolo[1.5-a]-pyrimidine

A mixture of 5.80 g (30 mmoles) of6-(2-hydroxyethyl)-5-methylpyrazolo[1,5-a]pyrimidin-7(4H)-one (preparedas described in Example 1) and 30 ml of phosphorous oxychloride washeated under reflux for 4 hours, with stirring. The reaction mixture wasthen poured into ice-water and extracted with chloroform. The extractwas washed with water and dried over anhydrous magnesium sulfate, afterwhich it was concentrated by evaporation under reduced pressure. Theresidue was purified by column chromatography through silica gel (elutedwith chloroform) and recrystallized from hexane, to afford 5.5 g (yield80%) of the title compound as light yellow prisms, melting at 87°-88° C.

¹ H-Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

2.71 (3H, singlet);

3.18-3.50 (2H, multiplet);

3.60-3.97 (2H, multiplet);

6.68 (1H, doublet, J=2.5 Hz);

8.17 (1H, doublet, J=2.5 Hz).

EXAMPLE 4

Following a similar procedure to that described in Example 3, 1.77 g(yield 57.8%) of7-chloro-6-(2-chloroethyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidinewas prepared as yellow needles, melting at 147°-149° C.

EXAMPLE 53-Bromo-7-chloro-6-(2-chloroethyl)-5-methylpyrazolo[1,5-a]-pyrimidine

2.35 g (13.2 mmoles) of N-bromosuccinimide was added to a solution of2.53 g (11 mmoles) of7-chloro-6-(2-chloroethyl)-5-methylpyrazolo[1,5-a]pyrimidine (preparedas described in Example 3) dissolved in 20 ml of chloroform, and themixture was heated under reflux, with stirring, for 30 minutes. At theend of this time, the reaction mixture was washed with a 2N aqueoussolution of potassium hydroxide and then with water, after which it wasdried over anhydrous sodium sulfate and then concentrated by evaporationunder reduced pressure. The residue was purified by columnchromatography through alumina (eluted with chloroform) andrecrystallized from diisopropyl ether to afford 3.33 g (yield 98%) ofthe title compound as colorless needles, melting at 128.5°-129.5° C.

¹ H-Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

2.77 (3H, singlet);

3.20-3.50 (2H, multiplet);

3.63-3.97 (2H, multiplet);

8.18 (1H, singlet).

EXAMPLE 63,7-Dichloro-6-(2-chloroethyl)-5-methylpyrazolo[1,5-a]-pyrimidin

1.60 g (12 mmoles) of N-chlorosuccinimide were added to a solution of2.30 g (10 mmoles) of7-chloro-6-(2-chloroethyl)-5-methylpyrazolo[1.5-a]pyrimidine (preparedas described in Example 3) in 10 ml of chloroform, and the resultingmixture was heated under reflux, with stirring, for one hour. At the endof this time, the reaction mixture was washed with a 2N aqueous solutionof potassium hydroxide and then with water, after, which it was driedover anhydrous sodium sulfate and then concentrated by evaporation underreduced pressure. The residue was purified by column chromatographythrough alumina (eluted with chloroform) and recrystallized fromdiisopropyl ether to afford 1.56 g (yield 59%) of the title compound aslight yellow needles, melting at 115°-117° C.

¹ H-Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

2.77 (3H, singlet);

3.13-3.52 (2H, multiplet);

3.63-3.98 (2H, multiplet);

8.18 (1H, singlet).

EXAMPLE 78-Benzyl-7,8-dihydro-5-methyl-6H-pyrazolo[1,5-a]pyrrolo-[3,2-e]pyrimidine

A solution of 1.15 g (5 mmoles) of7-chloro-6-(2-chloroethyl)-5-methylpyrazolo[1,5-a]pyrimidine (preparedas described in Example 3), 643 mg (6 mmoles) of benzylamine and 2 ml oftriethylamine dissolved in 5 ml of isopropanol was heated under refluxfor 7 hours, with stirring. The reaction mixture was then poured intowater and extracted with ethyl acetate. The organic layer was extractedwith 5% by volume aqueous sulfuric acid, and the extract was made basicby the addition of sodium carbonate. The crystals which precipitatedwere collected by filtration and washed with water. They were thenpurified by column chromatography through silica gel (eluted withchloroform) and recrystallized from a mixture of ethyl acetate andchloroform, to afford 788 mg (yield 60%) of the title compound ascolorless needles, melting at 130°-130.5° C.

¹ H-Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

2.38 (3H, singlet);

2.80-3.25 (2H, multiplet);

3.40-3.81 (2H, multiplet);

6.37 (1H, doublet, J=2.5 Hz);

8.01 (1H, doublet, J=2.5 Hz).

EXAMPLE 8

Following a similar procedure to that described in Example 7, 956 mg(yield 68%) of3-bromo-7,8-dihydro-8-ethyl-5-methyl-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidinewere prepared as light yellow needles, melting at 163°-165° C.

¹ H-Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

2.38 (3H, singlet);

3.05 (2H, triplet, J=9 Hz);

3.82 (2H, triplet, J=9 Hz);

7.93 (1H, singlet).

EXAMPLE 9

Following a similar procedure to that described in Example 7, 1.296 g(yield 49%) of8-(t-butyl)-3-chloro-7,8-dihydro-5-methyl-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]-pyrimidinewas prepared as light yellow prisms, melting at 132.5°-134° C.

¹ H-Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

2.40 (3H singlet);

2.97 (2H, triplet, J=9 Hz);

4.00 (2H, triplet, J=9 Hz);

7.93 (1H, singlet).

EXAMPLE 10

Following a similar procedure to that described in Example 7, 1.366 g(yield 73%) of3-bromo-7,8-dihydro-8-(4-methoxybenzyl)-5-methyl-6H-pyrazolo[1,5-a]pyrrolo-[3,2-e]pyrimidinewas prepared as light yellow needles, melting at 147°-149° C.

¹ H-Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

2.38 (3H, singlet);

3.02 (2H, multiplet);

3.68 (2H, multiplet);

8.00 (1H, singlet).

EXAMPLE 11

Following a similar procedure to that described in Example 7, 1.70 g(yield 32.4%) of3-bromo-8-cycloheptyl-7,8-dihydro-5-methyl-6H-pyrazolo[1,5-a]pyrrolo-[3,2-e]pyrimidinewas prepared as colorless needles, melting at 184°-185° C.

¹ H-Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

2.36 (3H, singlet);

3.02 (2H, multiplet);

3.82 (2H, multiplet);

7.90 (1H, singlet).

EXAMPLE 12

Following a similar procedure to that described in Example 7, 2.57 g(yield 61.6%) of8-ethyl-7,8-dihydro-5-methyl-2-phenyl-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]-pyrimidinewas prepared as light yellow needles, melting at 197°-198.5° C.

EXAMPLE 133-bromo-8-ethyl-5-methyl-8H-pyrazolo[1.5-a]pyrrolo-[3.2-e]pyrimidine

2.16 g (8.92 mmoles) of benzoyl peroxide were added to a solution of2.50 g (8.89 mmoles) of3-bromo-7,8-dihydro-8-ethyl-5-methyl-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine(prepared as described in Example 8) dissolved in 30 ml of benzene, andthe mixture was stirred for 2 hours. At the end of this time, thereaction mixture was washed with a 5% v/v aqueous solution of sodiumbicarbonate and then with water, after which it was dried over anhydroussodium sulfate and then concentrated by evaporation under reducedpressure. The residue was purified by column chromatography throughsilica gel (eluted with choloroform) and recrystallized from diisopropylether to afford 1.019 g (yield 41%) of the title compound as lightyellow needles, melting at 113°-114° C.

¹ H-Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

2.78 (3H, singlet);

6.61 (1H, doublet, J=3.5 Hz);

6.68 (1H, doublet, J=3.5 Hz);

8.02 (1H, singlet).

EXAMPLE 14

Following a similar procedure to that described in Example 13, 1.10 g(yield 73.8%) of8-ethyl-5-methyl-2-phenyl-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine wasprepared as light yellow prisms, melting at 142°-143.5° C.

EXAMPLE 153,7-Dibromo-8-ethyl-5-methyl-8H-pyrazolo[1,5-a]pyrrolo-[3,2-e]pyrimidine

N-bromosuccinimide was added at room temperature to a solution of 1.675g (6 mmoles) of3-bromo-8-ethyl-5-methyl-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine(prepared as described in Example 13) dissolved in 12 ml of chloroform,and the mixture was stirred for 2 hours. At the end of this time, thereaction mixture was washed with a 2N aqueous solution of potassiumhydroxide and then with water, after which it was dried over anhydroussodium sulfate and then concentrated by evaporation under reducedpressure. The residue was purified by column chromatography throughsilica gel (eluted with chloroform) and recrystallized from ethylacetate to afford 1.72 g (yield 80%) of the title compound as colorlessneedles, melting at 135°-137° C.

¹ H-Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

2.72 (3H, singlet);

6.68 (1H, singlet);

7.98 (1H, singlet).

We claim:
 1. A method of treating or alleviating the effects of cachexiacomprising administering to a mammal an effective amount of an activeagent sufficient to alleviate at least one effect selected from thegroup consisting of weight loss, depression of emotion, depression ofappetite, disorder of lipid metabolism, piloerection, decreased responseto chemotherapy and decreased response to radiotherapy, wherein saidactive agent is at least one enhancer of the activity of lipoproteinlipase selected from the group consisting of compounds of formula (Ia):##STR20## in which R¹ represents a hydrogen atom, a C₁ -C₅ alkly groupor a C₆ -C₁₀ carbocyclic aryl group which is unsubstituted or has atleast one substituent selected from the group consisting of substituents(a), defined below;R³ represents a C₁ -C₅ alkyl group or a C₃ -C₇cycloalkyl group; R^(4') represents a hydrogen atom, a hydroxy group ora C₁ -C₅ alkyl group; R^(5') represents a hydrogen atom, a hydroxygroup, an oxygen atom or a C₁ -C₅ alkyl group; and R^(6') represents ahydrogen atom, C₁ -C₁₅ alkyl group, a C₁ -C₅ alkyl group having at leastone substituent selected from the group consisting of substituents (b),defined below, a C₃ -C₇ alkenyl group, a C₃ -C₁₀ cycloalkyl group, a C₆-C₁₀ carbocyclic aryl group which is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (a),defined below, or an aralkyl group in which the alkyl part is C₁ -C₃ andthe aryl part is a C₆ -C₁₀ carbocyclic aryl group which is unsubstitutedor has at least one substituent selected from the group consisting ofsubstituents (c), defined below;substituents (a): C₁ -C₅ alkyl groups,halogen atoms, C₁ -C₅ alkoxy groups and sulfamoyl groups;substituents(b): halogen atoms, hydroxy groups, mercapto groups, dialkylamino groupsin which each alkyl part is C₁ -C₅ and is unsubstituted or has at leastone hydroxy substituent, heterocyclic groups as defined below, phenoxygroups, C₁ -C₅ alkoxy groups; C₁ -C₅ hydroxyalkoxy groups, benzoylgroups, substituted benzoyl groups having at least one substituentselected from the group consisting of substituents (d), defined below,benzoyloxy groups, substituted benzoyloxy groups having at least onesubstituent selected from the group consisting of substituents (d),defined below, and heterocyclic-carbonyloxy groups in which theheterocyclic part has from 5 to 6 ring atoms of which 1 or 2 arenitrogen hetero-atoms;substituents (c): C₁ -C₅ alkyl groups, halogenatoms and C₁ -C₅ alkoxy groups;substituents (d): halogen atoms and C₁-C₅ alkoxy groups; said heterocyclic groups have from 5 to 6 ring atomsof which 1 is a nitrogen atom through which the group is attached to theremainder of the molecule and 0, 1 or 2 are additional hetero-atomsselected from the group consisting of nitrogen and oxygen hetero-atoms,said group being unsubstituted or having at least one C₁ -C₅ alkylsubstituent; and pharmaceutically acceptable salts thereof.
 2. Themethod of claim 1, whereinR¹ represents a hydrogen atom; a straight orbranched chain alkyl group containing from 1 to 5 carbon atoms; or acarbocyclic aryl group containing from 6 to 10 carbon atoms, the arylgroup being unsubstituted or having at least one substituent selectedfrom the group consisting of substituents (a), defined below; R³represents a straight or branched chain alkyl group containing from 1 to5 carbon atoms; or a cycloalkyl group containing from 3 to 7 carbonatoms: R^(4') represents a hydrogen atom; a hydroxy group; or a straightor branched chain alkyl group containing from 1 to 5 carbon atoms;R^(5') represents a hydrogen atom; a hydroxy group; or a straight orbranched chain alkyl group containing from 1 to 5 carbon atoms; R^(6')represents a hydrogen atom; a straight or branched chain alkyl groupcontaining from 1 to 15 carbon atoms; a substituted straight or branchedchain alkyl group containing from 1 to 5 carbon atoms and having atleast one substituent selected from the group consisting of substituents(b'), defined below; a cycloalkyl group containing from 3 to 10 carbonatoms; an alkenyl group containing from 3 to 7 carbon atoms; acarbocyclic aryl group containing from 6 to 10 carbon atoms which arylgroup is unsubstituted or has at least one substituent selected from thegroup consisting of substituents (a), defined below; or an aralkyl groupin which the alkyl part is C₁ -C₃ and the aryl part is a phenyl groupwhich is unsubstituted or has at least one substituent selected from thegroup consisting of substituents (c), defined below:substitutuents (a):C₁ -C₅ alkyl groups, halogen atoms, C₁ -C₅ alkoxy groups and sulfamoylgroups;substituents (b'): halogen atoms, hydroxy groups, mercaptogroups, dialkylamino groups in which each alkyl group has from 1 to 5carbon atoms and is unsubstituted or has at least one hydroxysubstituent, five- and six-membered heterocyclic groups which areunsubstituted or have at least one C₁ -C₅ alkyl substituent and whichadditionally contain 0, 1 or 2 nitrogen and/or oxygen atoms in the ring,phenoxy groups, alkoxy groups containing from 1 to 5 carbon atoms,benzoyl groups which are unsubstituted or have at least one substituentselected from the group consisting of substituents (d), defined in claim1, benzoyloxy groups which are unsubstituted or have at least onesubstituent selected from the group consisting of substituents (d),defined in claim 1, and heterocyclic-carbonyloxy groups in which theheterocyclic part has from 5 to 6 ring atoms of which 1 or 2 arenitrogen hetero-atoms; andsubstituents (c): C₁ -C₅ alkyl groups, halogenatoms and C₁ -C₅ alkoxy groups.
 3. The method of claim 1, wherein:R¹represents a hydrogen atom, a C₁ -C₃ alkyl group, or a phenyl group,which is unsubstituted or has at least one substituent selected from thegroup consisting of substituents (a'), defined below; R³ represents a C₁-C₃ alkyl group or a cycloalkyl group containing from 3 to 5 carbonatoms; R^(4') represents a hydrogen atom, a hydroxy group or a C₁ -C₃alkyl group; R^(5') represents a hydrogen atom, a hydroxy group or a C₁-C₃ alkyl group; R^(6') represents a hydrogen atom, a C₁ -C₁₂ alkylgroup, a C₁ -C₅ alkyl group having at least one substituent selectedfrom the group consisting of substituents (b"), defined below; analkenyl group containing from 3 to 5 carbon atoms; a cycloalkyl groupcontaining from 5 to 8 carbon atoms; a phenyl group which isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (a'), defined below; or an aralkyl group inwhich the alkyl part is a C₁ -C₃ alkyl group and the aryl part is aphenyl group which is unsubstituted or has at least one substituentselected from the group consisting of substituents (c'), definedbelow:substituents (a'): C₁ -C₃ alkyl, groups, halogen atoms, C₁ -C₃alkoxy groups and sulfamonyl groups:substituents (h"): hydroxy groups;dialkylamino groups in which each alkyl part is C₁ -C₅ and isunsubstituted or has at least one hydroxy substituent: heterocyclicgroups having from 5 to 6 ring atoms of which 1 is a nitrogen atomthrough which the group is attached to the remainder of the molecule and0, 1 or 2 are additional hetero-atoms selected from the group consistingof nitrogen and oxygen hetero-atoms, said group being unsubstituted orhaving at least one C₁ -C₅ alkyl substituent; phenoxy groups; C₁ -C₃alkoxy groups; benzoyloxy groups which are unsubstituted or have atleast one halogen and/or C₁ -C₃ alkoxy substituent; andheterocyclic-carbonyloxy groups in which the heterocyclic part has from5 to 6 ring atoms of which 1 or 2 are nitrogen hetero-atoms;substituents(c'): C₁ -C₃ alkyl groups, halogen atoms and C₁ -C₃ alkoxy groups. 4.The method of claim 3 wherein:R¹ represents a hydrogen atom; a methylgroup; a phenyl group which is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (a"),defined below: R³ represents a methyl group or a cyclopropyl group;R^(4') represents a hydrogen atom or a methyl group: R^(5') represents ahydrogen atom or a C₁ -C₃ alkyl group; R^(6') represents a hydrogenatom; a C₁ -C₁₂ alkyl group; a C₁ -C₅ alkyl group having at least onesubstituent selected from the group consisting of substituents (b"),defined in claim 3; an alkenyl group containing from 3 to 5 carbonatoms; a cycloalkyl group containing from 5 to 8 carbon atoms; anunsubstituted phenyl group; a substituted phenyl group which has atleast one substituent selected from the group consisting of halogenatoms and sulfamoyl groups; or an aralkyl group in which the alkyl partis a C₁ -C₃ alkyl group and the aryl part is a phenyl group which isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (c'), defined in claim 3;substituents (a"):halogen atoms and C₁ -C₃ alkoxy groups.
 5. The method of claim 3,wherein:R¹ represents a hydrogen atom or a phenyl group which isunsubstituted or has at least one substituent selected from the groupconsisting of C₁ -C₃ alkoxy groups; R³ represents a methyl orcyclopropyl group; R^(4') represents a hydrogen atom; R^(5') representsa hydrogen atom or a C₁ -C₃ alkyl group; R^(6') represents a C₁ -C₁₂alkyl group; a C₁ -C₅ alkyl group having at least one substituentselected from the group consisting of substituents (b"'), defined below;an alkenyl group containing from 3 to 5 carbon atoms; a cycloalkyl groupcontaining from 5 to 8 carbon atoms; or an aralkyl group in which thealkyl part is a C₁ -C₃ alkyl group and the aryl part is a phenyl groupwhich is unsubstituted or has at least one substituent selected from thegroup consisting of substituents (c'), defined in claim 3;substituents(b"'): hydroxy groups; heterocyclic groups having from 5 to 6 ring atomsof which 1 is a nitrogen atom through which the group is attached to theremainder of the molecule and 0, 1 or 2 are additional hetero-atomsselected from the group consisting of nitrogen and oxygen hetero-atoms;phenoxy groups; benzoyloxy groups which are unsubstituted or have atleast one substituent selected from the group consisting of halogenatoms and C₁ -C₃ alkoxy groups; and heterocyclic-carbonyloxy groups inwhich the heterocyclic part has from 5 to 6 ring atoms of which 1 or 2are nitrogen hetero-atoms.
 6. The method of claim 1, in which saidactive agent is selected from the group consisting of8-butyl-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidineand pharmaceutically acceptable salts thereof.
 7. The method of claim 1,in which said active agent is selected from the group consisting of8-t-butyl-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidineand pharmaceutically acceptable salts thereof.
 8. The method of claim 1,in which said active agent is selected from the group consisting of8-t-butyl-5-cyclopropyl-7,8-dihydro-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidineand pharmaceutically acceptable salts thereof.
 9. The method of claim 1,in which said active agent is selected from the group consisting of7,8-dihydro-5-methyl-8-c-pentyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidineand pharmaceutically acceptable salts thereof.
 10. The method of claim1, in which said active agent is selected from the group consisting of8-heptyl-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidineand pharmaceutically acceptable salts thereof.
 11. The method of claim1, in which said active agent is selected from the group consisting of8-cycloheptyl-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidineand pharmaceutically acceptable salts thereof.
 12. The method of claim1, in which said active agent is selected from the group consisting of8-cyclooctyl-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidineand pharmaceutically acceptable salts thereof.
 13. The method of claim1, in which said active agent is selected from the group consisting of7,8-dihydro-5-methyl-8-(4-methylbenzyl)-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidineand pharmaceutically acceptable salts thereof.
 14. The method of claim1, in which said active agent is selected from the group consisting of7,8-dihydro-8-(4-methoxybenzyl)-5-methyl-6H-pyrrolo[3,2-e][1,2,4]-triazolo[1,5-a]pyrimidine and pharmaceutically acceptable salts thereof.
 15. Themethod of claim 1, in which said active agent is selected from the groupconsisting of8-(4-chlorobenzyl)-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidineand pharmaceutically acceptable salts thereof.
 16. The method of claim1, in which said active agent is selected from the group consisting of7,8-dihydro-5-methyl-8-(α-methylbenzyl)-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidineand pharmaceutically acceptable salts thereof.
 17. The method of claim1, in which said active agent is selected from the group consisting of7,8-dihydro-5-methyl-8-(1-methyl-2-phenoxyethyl)-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidineand pharmaceutically acceptable salts thereof.